New Ideas on PsA Pathogenesis May Drive New Treatments

NEW YORK — Over the past year, new evidence has emerged in support of the idea that psoriatic arthritis (PsA) is neither exclusively immune mediated nor a classic autoimmune disease, but that both mechanisms may be essential in disease pathogenesis, and that innate immune cells may possess adaptive properties that may lead to worsening of inflammation of the skin and joints.

Recent findings help dermatologists and rheumatologists to better understand the pathogenesis of PsA and may lead to more targeted and personalized therapies, Christopher Ritchlin, MD, MPH, who’s led research into the pathogenesis of inflammatory diseases, reported at the NYU Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis.

Psoriasis and PsA, along with ankylosing spondylitis and Crohn’s disease, have been thought to be either immune mediated or a classic autoimmune disorder, Ritchlin, a rheumatologist and internist and director of the Clinical Immunology Research Unit at the University of Rochester, Rochester, New York, told Medscape Medical News. “But emerging data reveal that these disorders might be triggered and sustained by both autoimmune and immune-mediated events,” he said.

Autoimmunity vs Immune Mediated

Autoimmune diseases are characterized by a specific autoantigen and antibody, such as the anti–cyclic citrullinated peptide antibody seen in rheumatoid arthritis, Ritchlin said. He cited a 2023 literature review from Italy that identified five autoantibodies and polymorphisms in PsA.

“In an immune-mediated disease, we demonstrate profound dysregulation of immune cells that promote inflammation, but we have not identified a specific autoantigen,” he said. “There’s an inflammatory response, which can be very severe, but we don’t know if it’s responding to an autoantigen or it’s just dysregulation of the T cells or the B cells or both.”

In a humanized mouse model developed by Maria Garcia-Hernandez, PhD, in Ritchlin’s lab, researchers found that both immunoglobulins and immune cells are required to recapitulate the skin and joint phenotypes. Ritchlin said that further analyses identified a putative autoantigen, which current experiments now underway are looking to confirm and should help discern distinctions in pathogenesis between a response to an autoantigen or cell dysregulation.

“There may be more than one type of immune inflammatory reaction that’s ongoing in individual tissue, and it may be different from one tissue to another,” Ritchlin told Medscape Medical News.

The immune-mediated and autoimmune properties of PsA are important to investigate, Jose U. Scher, MD, director of the Arthritis Clinic and Psoriatic Arthritis Center at NYU Langone Health in New York City, told Medscape Medical News.

“Classically considered an autoimmune disease, [PsA] may be better classified as an immune-mediated inflammatory disease,” Scher said. He noted one feature that makes PsA differ from classic autoimmunity is that it does not affect women predominantly.

“The fundamental question is whether there are elements of classic autoimmunity such as B cells that should be integrated into the research for future identification of novel therapeutics,” Scher said.

The ‘Additional Mechanism’

The additional mechanism Ritchlin referred to is “this idea of trained immunity,” he said, “where innate immune cells — fibroblasts, monocytes, keratinocytes — that are not considered to have [the] adaptive memory characteristic of T cells and B cells but act in an environment of inflammation and can actually develop sustained altered phenotypes in response to inflammation.”

A 2024 report from Europe outlined four characteristics of trained immunity, Ritchlin said, including that it is “antigen agnostic” and results from long-term reprogramming of cells through epigenetic and metabolic mechanisms. The effects of trained immunity are shorter in duration than that of classical adaptive immunity, he said.

These reprogrammed innate immune cells “retain a form of ‘memory’ after an initial stimulus, which can lead to enhanced or altered responses upon subsequent challenges,” Scher said.

In the context of PsA, Scher said, monocytes that express heightened inflammatory responses driven by metabolic and epigenetic reprogramming can become “trained” by triggers such as infections, cytokines (such as interleukin [IL]-1β and IL-17), or damage-associated molecular patterns that have been epigenetically modified to respond at higher rates in a future encounter with exacerbated production of proinflammatory cytokines, persistent inflammation, and flares.

Ritchlin explained how this emerging understanding of the mechanisms driving psoriasis and PsA is driving research into treatments.

“If you know that monocytes are undergoing change — these are innate cells, they’re not antigen driven — but that change is based on some type of pathway that makes the cell more inflammatory, then you can think about trying to block that pathway,” he said.

The goal would be to normalize the cellular environment that’s otherwise becoming activated to create the signs and symptoms of psoriasis and PsA, he said.

The other potential therapeutic target would be T cells, Ritchlin said. “There now are T cells that have been identified that have very specific alpha-beta receptors that are expanded in the peripheral blood, uveal fluid, and joints of HLAB27-positive patients with ankylosing spondylitis and anterior uveitis, which is thought to be immune mediated, not autoimmune,” he said.

Those HLAB27-positive patients “have expansion of a certain subtype of T cells, they have a specific receptor, and specific autoantigens have been identified pointing to a potential autoimmune response,” Ritchlin added.

An antibody that binds and removes specific T-cell receptor subsets may be an effective strategy without being immunosuppressive, Ritchlin said. “That’s real exciting, and we’re all hoping that is going to be a therapeutic approach that could be successful,” he said.

Ritchlin disclosed financial relationships with AbbVie, Amgen, Bristol Myers Squibb, Janssen, Novartis, Pfizer, and UCB. Scher had no relevant financial relationships.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.